scholarly journals Mutagenic Consequences of Sublethal Cell Death Signaling

2021 ◽  
Vol 22 (11) ◽  
pp. 6144
Author(s):  
Christine J. Hawkins ◽  
Mark A. Miles
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Cancer Cells ◽  
Apoptotic Cell ◽  
Oncogenic Potential ◽  
Genomic Changes ◽  
Cell Death Pathways ◽  
Anti Cancer ◽  
Cell Death Signaling ◽  
Mechanisms Of Mutagenesis

Many human cancers exhibit defects in key DNA damage response elements that can render tumors insensitive to the cell death-promoting properties of DNA-damaging therapies. Using agents that directly induce apoptosis by targeting apoptotic components, rather than relying on DNA damage to indirectly stimulate apoptosis of cancer cells, may overcome classical blocks exploited by cancer cells to evade apoptotic cell death. However, there is increasing evidence that cells surviving sublethal exposure to classical apoptotic signaling may recover with newly acquired genomic changes which may have oncogenic potential, and so could theoretically spur the development of subsequent cancers in cured patients. Encouragingly, cells surviving sublethal necroptotic signaling did not acquire mutations, suggesting that necroptosis-inducing anti-cancer drugs may be less likely to trigger therapy-related cancers. We are yet to develop effective direct inducers of other cell death pathways, and as such, data regarding the consequences of cells surviving sublethal stimulation of those pathways are still emerging. This review details the currently known mutagenic consequences of cells surviving different cell death signaling pathways, with implications for potential oncogenic transformation. Understanding the mechanisms of mutagenesis associated (or not) with various cell death pathways will guide us in the development of future therapeutics to minimize therapy-related side effects associated with DNA damage.

scholarly journals Identification and Characterization of the Caspase-Mediated Apoptotic Activity of Teucrium mascatense and an Isolated Compound in Human Cancer Cells

Molecules ◽  
2019 ◽  
Vol 24 (5) ◽  
pp. 977 ◽  
Author(s):  
Neena Panicker ◽  
Sameera Balhamar ◽  
Shaima Akhlaq ◽  
Mohammed Qureshi ◽  
Tania Rizvi ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Apoptotic Cell ◽  
Human Cancer ◽  
Annexin V ◽  
Dependent Manner ◽  
Human Cancer Cells ◽  
Cell Death Pathways ◽  
Proliferative Effect ◽  
Mcf 7

Plants of the genus Teucrium (Lamiaceae or Labiatae family) are known historically for their medicinal value. Here, we identify and characterize the anticancer potential of T. mascatense and its active compound, IM60, in human cancer cells. The anti-proliferative effect of a T. mascatense methanol extract and its various fractions were analyzed in MCF-7 and HeLa cells in a dose- and time dependent manner. The dichloromethane fraction (TMDF) was observed to be the most effective with cytotoxicity against a more expanded series of cell lines, including MDA-MB-231. A time and dose-dependent toxicity profile was also observed for IM60; it could induce rapid cell death (within 3 h) in MCF-7 cells. Activation of caspases and PARP, hallmarks of apoptotic cell death pathways, following treatment with TMDF was demonstrated using western blot analysis. Inversion of the phosphatidylserine phospholipid from the inner to the outer membrane was confirmed by annexin V staining that was inhibited by the classical apoptosis inhibitor, Z-VAK-FMK. Changes in cell rounding, shrinkage, and detachment from other cells following treatment with TMDF and IM60 also supported these findings. Finally, the potential of TMDF and IM60 to induce enzymatic activity of caspases was also demonstrated in MCF-7 cells. This study, thus, not only characterizes the anticancer potential of T. mascatense, but also identifies a lead terpenoid, IM60, with the potential to activate anticancer cell death pathways in human cancer cells.

scholarly journals Opportunities for Ferroptosis in Cancer Therapy

Antioxidants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 986
Author(s):  
Kenji M. Fujihara ◽  
Bonnie Z. Zhang ◽  
Nicholas J. Clemons
Keyword(s):  
Lipid Peroxidation ◽  
Cell Death ◽  
Cancer Therapy ◽  
Cancer Cells ◽  
Therapeutic Strategy ◽  
Molecular Mechanisms ◽  
Apoptotic Cell ◽  
Cancer Therapeutics ◽  
Therapeutic Window ◽  
Anti Cancer

A critical hallmark of cancer cells is their ability to evade programmed apoptotic cell death. Consequently, resistance to anti-cancer therapeutics is a hurdle often observed in the clinic. Ferroptosis, a non-apoptotic form of cell death distinguished by toxic lipid peroxidation and iron accumulation, has garnered substantial attention as an alternative therapeutic strategy to selectively destroy tumours. Although there is a plethora of research outlining the molecular mechanisms of ferroptosis, these findings are yet to be translated into clinical compounds inducing ferroptosis. In this perspective, we elaborate on how ferroptosis can be leveraged in the clinic. We discuss a therapeutic window for compounds inducing ferroptosis, the subset of tumour types that are most sensitive to ferroptosis, conventional therapeutics that induce ferroptosis, and potential strategies for lowering the threshold for ferroptosis.

Ouabain induces apoptotic cell death in human prostate DU 145 cancer cells through DNA damage and TRAIL pathways

2019 ◽  
Vol 34 (12) ◽  
pp. 1329-1339 ◽  
Author(s):  
Yi‐Ming Chang ◽  
Yung‐Luen Shih ◽  
Chao‐Ping Chen ◽  
Ko‐Lin Liu ◽  
Mei‐Hui Lee ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Cancer Cells ◽  
Apoptotic Cell ◽  
Apoptotic Cell Death ◽  
Human Prostate

scholarly journals Combination of Arsenic Trioxide and Valproic Acid Efficiently Inhibits Growth of Lung Cancer Cells via G2/M-Phase Arrest and Apoptotic Cell Death

2020 ◽  
Vol 21 (7) ◽  
pp. 2649
Author(s):  
Hyun Kyung Park ◽  
Bo Ram Han ◽  
Woo Hyun Park
Keyword(s):  
Lung Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Apoptotic Cell ◽  
Apoptotic Cell Death ◽  
Lung Cancer Cells ◽  
Phase Arrest ◽  
Anti Cancer ◽  
M Phase

Arsenic trioxide (ATO; As2O3) has anti-cancer effects in various solid tumors as well as hematological malignancy. Valproic acid (VPA), which is known to be a histone deacetylase inhibitor, has also anti-cancer properties in several cancer cells including lung cancer cells. Combined treatment of ATO and VPA (ATO/VPA) could synergistically enhance anti-cancer effects and reduce ATO toxicity ATO. In this study, the combined anti-cancer effects of ATO and VPA (ATO/VPA) was investigated in NCI-H460 and NCI-H1299 lung cancer cells in vitro and in vivo. A combination of 3 μM ATO and 3 mM VPA (ATO/VPA) strongly inhibited the growths of both lung cancer cell types. DNA flow cytometry indicated that ATO/VPA significantly induced G2/M-phase arrest in both cell lines. In addition, ATO/VPA strongly increased the percentages of sub-G1 cells and annexin V-FITC positive cells in both cells. However, lactate dehydrogenase (LDH) release from cells was not increased in ATO/VPA-treated cells. In addition, ATO/VPA increased apoptosis in both cell types, accompanied by loss of mitochondrial membrane potential (MMP, ∆Ψm), activation of caspases, and cleavage of anti-poly ADP ribose polymerase-1. Moreover, a pan-caspase inhibitor, Z-VAD, significantly reduced apoptotic cell death induced by ATO/VPA. In the xenograft model, ATO/VPA synergistically inhibited growth of NCI-H460-derived xenograft tumors. In conclusion, the combination of ATO/VPA effectively inhibited the growth of lung cancer cells through G2/M-phase arrest and apoptotic cell death, and had a synergistic antitumor effect in vivo.

scholarly journals Apoptotic Cell Death Induction Through Pectin, Guar Gum and Zinc Oxide Nanocomposite in A549 Lung Adenocarcinomas

2021 ◽  
Vol 12 (2) ◽  
pp. 1856-1869
Keyword(s):  
Cell Death ◽  
Zinc Oxide ◽  
Cancer Cells ◽  
Guar Gum ◽  
Apoptotic Cell ◽  
Human Peripheral Blood ◽  
Reactive Oxygen Species Generation ◽  
A549 Cells ◽  
Target Cells ◽  
Anti Cancer

Previously, we reported the immunostimulatory potential of the nanocomposite prepared from biopolymers (Pectin and Guar gum) and zinc oxide (Pec-gg-ZnO) on human peripheral-blood lymphocytes leading to enhanced anti-cancer immunity. The current study aims to describe the direct anti-cancer potential of Pec-gg-ZnO nanocomposite and the relevant mechanism of cell death induction in human lung carcinomas (A549). The cytotoxicity assay revealed the anti-cancer potential of Pec-gg-ZnO nanocomposite towards A549 cells, cervical adenocarcinoma (HeLa), and prostatic small cell carcinoma (PC-3). The IC50 values were 83.67 ± 0.10 μg/ml, 87.25 ± 0.03 μg/ml and 85.95 ± 0.03 μg/ml for A549, HeLa and PC-3 cells, respectively. The nanocomposite's cancer cells' killing capabilities were significantly higher than pectin and guar gum alone. Hemolysis assay revealed that synthesized Pec-gg-ZnO nanocomposite is biocompatible at 2.5 mg/ml. S phase arrest with enhanced sub-G1 (apoptotic cells) population was examined in A549 cells treated with Pec-gg-ZnO nanocomposite. The nanocomposite caused apoptosis of target cells by inducing mitochondrial depolarisation, reactive oxygen species generation, caspase-3 and Poly (ADP-ribose) polymerase 1 (PARP1) activation resulting in DNA fragmentation. Collectively, the current data revealed that Pec-gg-ZnO nanocomposite is a novel polymer-based anti-cancer agent capable of inducing apoptotic pathways in cancer cells.

scholarly journals Mitochondrial glutamine metabolism regulates sensitivity of cancer cells after chemotherapy via amphiregulin

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Sunsook Hwang ◽  
Seungyeon Yang ◽  
Minjoong Kim ◽  
Youlim Hong ◽  
Byungjoo Kim ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Cancer Cells ◽  
Dna Damage Response ◽  
Transcriptional Activation ◽  
Metabolic Response ◽  
Apoptotic Cell ◽  
Glutamine Metabolism ◽  
Damage Response

AbstractThe DNA damage response is essential for sustaining genomic stability and preventing tumorigenesis. However, the fundamental question about the cellular metabolic response to DNA damage remains largely unknown, impeding the development of metabolic interventions that might prevent or treat cancer. Recently, it has been reported that there is a link between cell metabolism and DNA damage response, by repression of glutamine (Gln) entry into mitochondria to support cell cycle arrest and DNA repair. Here, we show that mitochondrial Gln metabolism is a crucial regulator of DNA damage-induced cell death. Mechanistically, inhibition of glutaminase (GLS), the first enzyme for Gln anaplerosis, sensitizes cancer cells to DNA damage by inducing amphiregulin (AREG) that promotes apoptotic cell death. GLS inhibition increases reactive oxygen species production, leading to transcriptional activation of AREG through Max-like protein X (MLX) transcription factor. Moreover, suppression of mitochondrial Gln metabolism results in markedly increased cell death after chemotherapy in vitro and in vivo. The essentiality of this molecular pathway in DNA damage-induced cell death may provide novel metabolic interventions for cancer therapy.

scholarly journals Axl Inhibitor R428 Enhances TRAIL-Mediated Apoptosis Through Downregulation of c-FLIP and Survivin Expression in Renal Carcinoma

2019 ◽  
Vol 20 (13) ◽  
pp. 3253 ◽  
Author(s):  
Seon Min Woo ◽  
Kyoung-jin Min ◽  
Seung Un Seo ◽  
Shin Kim ◽  
Peter Kubatka ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Renal Carcinoma ◽  
Apoptotic Cell ◽  
Survivin Expression ◽  
Human Skin Fibroblast ◽  
Cancer Drugs ◽  
Survivin Protein ◽  
Anti Cancer ◽  
Induced Apoptosis

R428, a selective small molecule Axl inhibitor, is known to have anti-cancer effects, such as inhibition of invasion and proliferation and induction of cell death in cancer cells. The Axl receptor tyrosine kinase is highly expressed in cancer cells and the level of Axl expression is associated with survival, metastasis, and drug resistance of many cancer cells. However, the effect of Axl inhibition on overcoming anti-cancer drugs resistance is unclear. Therefore, we investigated the capability of Axl inhibition as a therapeutic agent for the induction of TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) sensitivity. In this study, R428 markedly sensitized cancer cells to TRAIL-induced apoptotic cell death, but not in normal human skin fibroblast (HSF) and human umbilical vein cells (EA.hy926). Moreover, knockdown of Axl by siRNA also increased TRAIL-induced apoptosis. R428 decreased c-FLIP proteins levels via induction of miR-708 expression and survivin protein levels at the post-translational level, and we found that knockdown of Axl also decreased both c-FLIP and survivin protein expression. Overexpression of c-FLIP and survivin markedly inhibited R428 plus TRAIL-induced apoptosis. Furthermore, R428 sensitized cancer cells to multiple anti-cancer drugs-mediated cell death. Our results provide that inhibition of Axl could improve sensitivity to TRAIL through downregulation of c-FLIP and survivin expression in renal carcinoma cells. Taken together, Axl may be a tempting target to overcome TRAIL resistance.

scholarly journals Synthesis and pharmacological characterization of glucopyranosyl-conjugated benzyl derivatives as novel selective cytotoxic agents against colon cancer

2021 ◽  
Vol 8 (2) ◽  
Author(s):  
Boqiao Fu ◽  
Yingjie Li ◽  
Shaoyong Peng ◽  
Xiaolin Wang ◽  
Jingying Hu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Apoptotic Cell ◽  
Cytotoxic Agents ◽  
Pharmacological Characterization ◽  
Anti Cancer ◽  
Colorectal Cancer Cells

Glucopyranosyl-conjugated benzyl derivatives containing a [1,2,3]-triazole linker were synthesized. Benzyl served as an important pharmacophore in anti-cancer compounds. Compound 8d inhibited the proliferation of colorectal cancer cells with the potency comparable to 5-fluorouracil (5-FU) with improved selectivity towards cancer cells. The antiproliferative activity of 8d is achieved through triggering apoptotic cell death.

scholarly journals Non-Apoptotic Cell Death Signaling Pathways in Melanoma

2020 ◽  
Vol 21 (8) ◽  
pp. 2980 ◽  
Author(s):  
Mariusz L. Hartman
Keyword(s):  
Cell Death ◽  
Signaling Pathways ◽  
Melanoma Cell ◽  
Apoptotic Cell ◽  
Genetic Alterations ◽  
Melanoma Cells ◽  
Apoptotic Cell Death ◽  
Specific Cell ◽  
Anti Cancer ◽  
Cell Death Signaling

Resisting cell death is a hallmark of cancer. Disturbances in the execution of cell death programs promote carcinogenesis and survival of cancer cells under unfavorable conditions, including exposition to anti-cancer therapies. Specific modalities of regulated cell death (RCD) have been classified based on different criteria, including morphological features, biochemical alterations and immunological consequences. Although melanoma cells are broadly equipped with the anti-apoptotic machinery and recurrent genetic alterations in the components of the RAS/RAF/MEK/ERK signaling markedly contribute to the pro-survival phenotype of melanoma, the roles of autophagy-dependent cell death, necroptosis, ferroptosis, pyroptosis, and parthanatos have recently gained great interest. These signaling cascades are involved in melanoma cell response and resistance to the therapeutics used in the clinic, including inhibitors of BRAFmut and MEK1/2, and immunotherapy. In addition, the relationships between sensitivity to non-apoptotic cell death routes and specific cell phenotypes have been demonstrated, suggesting that plasticity of melanoma cells can be exploited to modulate response of these cells to different cell death stimuli. In this review, the current knowledge on the non-apoptotic cell death signaling pathways in melanoma cell biology and response to anti-cancer drugs has been discussed.

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